A computational biologist's personal views on new technologies & publications on genomics & proteomics and their impact on drug discovery

Thursday, March 31, 2016

Reflections on And The Band Played On

Fellow blogger, colleague and science history buff Ash pointed out to me recently that Randy Shilt's And The Band Played On for Kindle was on sale. I hadn't read the book, nor seen the miniseries, so I snapped up a copy. It's a good read -- though at times a hard one - I don't believe I've ever read another work of non-fiction where such a high fraction of the named individuals are dead by the end of the book

And The Band Played On is a complex, chronological look at the early days of the AIDS epidemic, primarily from a U.S., perspective. One of the very early cases, a female Danish doctor who died mysteriously in the 1970s, does lead off the book and there is some discussion of a doctor in Paris who played a key role in the Pasteur Institute's work, but most of the book centers on the gay communities in New York and San Francisco, along with scientists at the CDC, NCI and NIH and politicians in Washington D.C.

A general summary of the book is very few people come out as heroes, and many come off as villains. Robert Gallo certainly comes off very, very badly, from the fight with the Pasteur Institute to squabbling with the CDC (including cutting off a former colleague from any access to NCI reagents, when that colleague took a position at the CDC). David Sencer, the New York City Commissioner of Health, perhaps comes off even worse -- someone who always chose miserly inaction as their path. . The few individuals who get overall positive treatment are those public health officials who struggled early on to get an alarm out and medical personnel who fought valiantly to treat patients in the face of official antipathy or outright antagonism.

Shilts conveys a rather complex attitude towards many political figures of the era. He portrays some of the Reagan administration figures as being reluctant participants in the effort to minimize funding. he also points out that while Surgeon General C. Everett Koop did deliver a principled report on AIDS that was a radical contrast to the Reagans' silence on the topic, he only did so after the epidemic had raged for years.

An interesting fact I learned from the Wikipedia entry on Shilts: he refused to have his doctor inform him of his HIV test results until he had completed the book. One can only wonder how much angrier the book would have been if he had know he was infected; Shilts would later succumb to the disease.

My Personal (Non)Experience With AIDS

I have been fortunate for this disease to have very little direct impact on me, in that as far as I know I've never known an infected individual. In some ways that seems very strange, given that AIDS has been a pervasive news item throughout my adult life. I got started on the topic a bit earlier: in 1985-86 school year I wrote a term paper on AIDS, which was just starting to hit the mainstream press. I don't have a copy, but I don't remember anything as graphic or searing as And the Band, which wouldn't appear until later. Apparently I was lucky to find anything to write on; the book makes clear that most U.S. news outlets (with particular ire directed at the New York Times) failed to print much of anything in the first several years of the epidemic.

My public high school was too conservative to broach the topic, but when I got to Delaware in Fall 1987 safe sex was quite a focus. When I was a summer intern, I had my one close encounter with HIV. Centocor had developed the first blood test kit, and the lab space used for this was still in place -- along with positive control blood samples. The space was to be remodeled for new purposes, so the samples needed to be cleared out -- and this was assigned to the intern. I remember a bit of heightened anxiety on my part, so I double-gloved, but in the end I was moving cardboard boxes of sealed vials into autoclave bags (I remember double-bagging as well), so the risk was extremely minimal.

On Journals and Publishing

If Shilts were alive today, there is no doubt where he would stand on pre-prints and open access -- several times he points out where peer review dragged out the public release of important information. In many cases, manuscripts were sent to prestigious journals such as New England Journal of Medicine or Lancet, and the authors were loathe to say anything about them for fear of running afoul of the embargo policies. And too often, the review would be slow and dragged out, and too often the papers would be rejected or severely abused before publication. Indeed, the book documents how scientists at the CDC did an end-run around the process to get out the first official word of AIDS, published in the CDC's Weekly Morbidity & Mortality Report, which was not peer-reviewed.

Pondering Sequencing Counterfactuals

AIDS appeared in the early 1980s, when sequencing was very different. Indeed, PCR didn't exist yet. This was a major contributor to Gallo's obnoxious powerplay with his subordinate: Gallo controlled antibodies, the only reagents available for detecting HIV infection.

I started thinking about trying to construct a proper counterfactual (aka alternative history) of AIDS and sequencing, but decided it is beyond my skill. To me, the most interesting counterfactuals tweak one small, plausible event. What if the newly elected FDR, rather than the mayor of Chicago sharing the podium, had been the one fatally struck in Chicago by an assassin's bullets? What if the Lost Order hadn't been lost? What if Operation Market Garden had included a coup de main glider assault on the Arnhem Bridge? Not all such ponderables are military in nature: what if Watson & Crick had never seen Rosalind Franklin's Photo 51?

Presumably a counterfactual would either place today's sequencing capacity in the early 1980s, or move AIDS to present times. The former is problematic: if you are packing your time machine, make sure you pack not only a sequencer and reagents, but also some serious computing hardware. Moving AIDS to now is perhaps more plausible -- except all of the effects that AIDS has had on society and science. On the other hand, new pathogens are showing up constantly, so perhaps AIDS waiting until now isn't totally implausible.

I pondered this while reading the book, with the result that my opinion shifted as new information came forward. Shilts points out that once the Pasteur Institute commited to isolating the virus, progress was actually quite rapid (I think the time he cites is about 3 months). However, it took a while for the Pasteur to commit. Other labs ran into roadblocks: Jay Levy could make a go at it because nobody at UCSF would let him use their ultracentrifuges for fear of contamination, and he couldn't get funding for a long while to get his own. Retrovirology had apparently been a waning field in terms of funding, so very few labs had the skills required. So perhaps the biggest leveling effect of high throughput sequencing would have been to broaden the number of labs which could have looked. Of course, it would still require looking at RNA to successfully find the virus.

Of course, there was a lot of resistance to the idea of a single infectious agent or even any infectious agent. Many blamed drug use, particularly stimulants known as poppers (alkyl nitrites). There was also the problem of the myriad opportunistic infections which struck AIDS patients. Could sequencing have more quickly shown that HIV was the commonality, with the other infections as more varying? Would this have convinced the scientific and medical community more quickly? That's the unanswerable ponderable.

Inexpensive, facile sequencing would have presumably also quickly squelched some of the confusion over the type of retrovirus. Gallo and Max Essex were both convinced the AIDS agent was similar to HTLV, and Gallo insisted on calling the virus HTLV-III long after it was shown to be a lentivirus. Indeed, the virus is known as HIV as a compromise; by typical practice the Pasteur's naming of LAV (Lymphadenopathy Associated Virus). Noisy antibody testing results appeared to give Gallo cover for this farce. (indeed, his group still called it HTLV-III when they had obtained hybridization evidence that it was a lentivirus) Of course, his appalling stunt of withholding antibodies wouldn't be nearly as effective with PCR in the picture; once the sequence of the virus was in the public sphere anyone can design and order primers!

A similar argument might be made that the coalescing of muttiple odd syndromes into a single unified AIDS model might have occurred sooner. Because the epidemic was first spotted as such amongst the gay populations of major U.S. cities such as New York, Los Angeles and San Francisco, other populations were initially ignored. A doctor in the New York area recognized his pediatric patients had similar symptoms to the emergent disease, but couldn't get anyone to believe him that these were not congenital immune deficiencies. Simple sequencing or PCR would have shown the virus being present, and sequencing could have also proven quickly that mother-child transmission was occurring. Heterosexual transmission, particularly female-to-male, was also greeted with excessive skepticism; sequencing might well have made disbelief untenable more quickly.

Perhaps the biggest impact of sequencing would have been proving sooner transmission via blood transfusions. Shilts reserves strong ire for the blood banks which actively resisted any sort of screening of blood. In the absence of knowledge of the AIDS agent, it was suggested that testing blood for Hepatitis B core antigen would be a useful proxy. Most blood banks, in Shilts' telling, hid behind the claim that proof of transmission via transfusion was not conclusive; finding the same strains in donor blood and recipients should have squashed that quickly.

One thing that sequencing has resolved is that Shilts placed far too much blame on Gaëtan Dugas, a Canadian airline steward who Shilts pinned as Patient Zero, spreading AIDS across the U.S.

Closing Thoughts

And The Band Plays On forms a third book I've read in the last year with a major look at AIDS: The Coming Plague and Level 4: Virus Hunters of the CDC being the other two. Each is complementary; Band covers the political aspects and the reaction of the U.S. gay community in depth, whereas The Coming Plague and Level 4 have much greater coverage of the epidemic in Africa (which is touched on in Band, but only a little). None of these cover drug development for AIDS very much; suggestions for a book in that space would be welcomed. Sadly, all three books document misinformed hysteria and political grandstanding over AIDS and other diseases (such as Ebola), which has repeated itself with last year's Ebola. Unfortunately, those in power who really should be reading these books probably never consider doing so.

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About Me

Dr. Robison spent 10 years at Millennium Pharmaceuticals working with various genomics & proteomics technologies & working on multiple teams attempting to apply these throughout the drug discovery process. He spent 2 years at Codon Devices working on a variety of protein & metabolic engineering projects as well as monitoring a high-throughput gene synthesis facility. After a brief bit of consulting, he rejoined the cancer drug discovery field at Infinity Pharmaceuticals in May 2009. In September 2011 he joined Warp Drive Bio, a startup applying genomics to natural product drug discovery. Other recurring characters in this blog are his loyal Shih Tzu Amanda and his teenaged son alias TNG (The Next Generation).
Dr. Robison can be reached via his Gmail account, keith.e.robison@gmail.com
You can also follow him on Twitter as @OmicsOmicsBlog.